Members of the protein kinase family of human enzymes play important regulatory roles in a multitude of distinct signal transduction processes due to their post-translational modification of specific proteins via the addition of a phosphate group (Hunter, Cell 1987, 50, 823-829). Bruton's tyrosine kinase (BTK) is a member of the Tec family of tyrosine kinases and plays a critical role in B cell development, activation and antibody production.
The contribution of BTK to B cell biology is exemplified in the X-linked agammaglobulinemia (XLA) immunodeficiency in humans (reviewed in Lindvall, Immunol. Rev. 2005, 203, 200-215) that display attenuated calcium signaling upon B cell receptor (BCR) engagement, lack mature B cells in the periphery due to block between pro- and pre-B cell stage and have lower levels of circulating antibodies than normal healthy subjects. The outcome of recent clinical trials with B cell depleting anti-CD20 molecules in diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS) support the hypothesis that B cells offer an important intervention node for controlling autoimmune disorders (Townsend, Immunol. Rev. 2010, 237, 264-283). As such, attenuation of B cell activation and proliferation via inhibition of BTK may offer similar therapeutic benefit and is consistent with the demonstrated resistance of BTK-deficient mice to collagen induced arthritis (Jansson, Clin. Exp. Immunol. 1993, 94, 459-465) and experimental autoimmune encephalitis (Svensson, Eur. J. Immunol. 2002, 32, 1939-1946 and Mangla, Blood 2004, 104, 1191-1197). Similarly, the clinical efficacy observed with a neutralizing antibody to the B cell stimulating factor BlyS supports a role for B cells in the pathophysiology of systemic lupus erythematosus (SLE) (La Cava, Expert Opin. Biol. Ther. 2010, 10, 1555-1561). Given the necessity for BTK for the production of autoantibodies, including anti-DNA antibodies, in murine models of SLE (Steinberg, J. Clin. Invest. 1982, 70, 587-597; Golding, J. Immunol. 1983, 130, 1043-1046; Scribner, J. Immunol. 1987, 138, 3611-3617; Seldin, J. Exp. Med. 1987, 166, 1585-1590; Takeshita, Int. Immunol. 1998, 10, 435-4444; Whyburn, J. Immunol. 2003, 171, 1850-1858), BTK inhibitors may offer therapeutic benefit to SLE patients.
Within myeloid cells, BTK signal transduction is necessary for the stimulated release of inflammatory cytokines such as TNFα from stimulated monocytes (Horwood, J. Exp. Med. 2003, 197, 1603-1611) and for optimal actin cytoskeletal organization and lacunar bone resorption in isolated osteoclasts (Danks, J. Bone Miner. Res. 2010, 26, 182-192). Bone marrow derived mast cells lacking BTK exhibit impaired activation-induced degranulation and cytokine release. Given the role of BTK in signal transduction processes across multiple cell types implicated in the pathogenesis of autoimmune and allergic disorders, inhibition of BTK activity may provide clinical benefit in diseases such as RA, MS, SLE, lupus nephritis, Sjogren's disease, vasculitis, asthma and allergic disorders.